Evaluation of disease‐mediated therapeutic protein–drug interactions between an anti–interleukin‐6 monoclonal antibody (sirukumab) and cytochrome P450 activities in a phase 1 study in patients with rheumatoid arthritis using a cocktail approach

Abstract

This therapeutic protein-drug interaction study evaluated the disease-mediated effect of sirukumab (anti-interleukin 6 [anti-IL-6] monoclonal antibody) on the pharmacokinetics of the cytochrome P450 (CYP) probe substrates midazolam (CYP3A), omeprazole (CYP2C19), warfarin (CYP2C9), and caffeine (CYP1A2) in patients with active rheumatoid arthritis (RA). Twelve patients with C-reactive protein (CRP) ≥ 8.0 mg/L at screening received oral administration of a CYP probe cocktail consisting of 0.03 mg/kg midazolam, 10 mg warfarin + 10 mg vitamin K (equivalent to 5 mg S-warfarin), 20 mg omeprazole, and 100 mg caffeine 1 week before and 1, 3, and 6 weeks after a single subcutaneous dose of 300 mg sirukumab. The results showed that the pharmacokinetics of midazolam, omeprazole, and S-warfarin were nonequivalent before and after the administration of a single dose of 300 mg sirukumab. Area under the plasma concentration-time curve (AUC0- ∞ ) for midazolam, omeprazole, and S-warfarin was reduced by 30%-35%, 37%-45%, and 18%-19%, respectively, after sirukumab administration. Caffeine AUC0-∞ was increased by 20%-34% after sirukumab administration. The effect of sirukumab on CYP substrates was sustained for at least 6 weeks. No new adverse drug reactions related to the administration of sirukumab were observed in this study. These results suggest that sirukumab may reverse IL-6-mediated suppression of CYP3A, CYP2C9, and CYP2C19 activities in patients with active RA.

Development of a Physiologically Based Pharmacokinetic Model to Predict Disease-Mediated Therapeutic Protein–Drug Interactions: Modulation of Multiple Cytochrome P450 Enzymes by Interleukin-6

“…The reported baseline systemic IL-6 concentrations were highly varied, ranging from 1.24-11 pg/mL in healthy subjects (16,17,(20)(21)(22)(23)(24)(25)(26) and from 3.51-119 pg/mL in RA patients (8,10,(14)(15)(16)(17)(18)(19)(20). Based on the pooled analysis using data available in the literature, the estimated average systemic IL-6 concentrations in healthy subjects was 3.27 ± 2.38 pg/mL (Fig.…”

“…Consistently, a recent in vivo drug-drug interaction (DDI) study conducted in RA patients showed that the administration of an anti-IL-6 receptor monoclonal antibody (mAb) tocilizumab reversed IL-6-induced suppression of CYP3A4 and CYP2C19 activity, as reflected by a significant decrease in systemic exposure to simvastatin (a CYP3A4 substrate) and omeprazole (a CYP2C19 substrate) following tocilizumab treatment (8,9). Another cocktail clinical DDI study conducted in RA patients also reported that treatment with an anti-IL-6 antibody sirukumab led to decreases in systemic exposure to CYP3A4 substrate midazolam, CYP2C19 substrate omeprazole, and CYP2C9 substrate S-warfarin but increases in systemic exposure to CYP1A2 substrate caffeine (10), further confirming the possibility of therapeutic protein-drug interactions (TP-DI) between anti-IL-6 therapeutic proteins (TPs) and smallmolecule drugs in RA patients via modulation of CYP enzymes.…”

“…Pharmacokinetic data were obtained from the sirukumab clinical cocktail TP-DI study (10), which was an open-label, phase 1 study in men and women aged 18-65 years, inclusive, who had a diagnosis of RA and screening C-reactive protein ≥8.0 mg/L. Twelve patients, genotyped to exclude poor metabolizers of CYP2C9 and CYP2C19, were enrolled.…”

“…Literature data regarding systemic levels of IL-6 were pooled together to determine the population mean with SD for systemic levels of IL-6 in RA patients (8,10,(14)(15)(16)(17)(18)(19)(20) and in healthy subjects (16,17,(20)(21)(22)(23)(24)(25)(26). The mean or individual IL-6 plasma or serum concentration values from different studies were combined, and associated variability was calculated with R (http://www.r-project.org) and Excel (Microsoft, Redmond, WA).…”

“…Then, several necessary drug-specific parameters of the CYP substrates, such as fraction of absorption, absorption rate constant, single-adjusting compartment, distribution clearance, and intrinsic hepatic clearance, for all or some of the CYP substrates were optimized using the parameter estimation function and automated sensitivity analysis functions of the ADME simulator (Table II). Subsequently, plasma concentration profiles of the CYP substrates in RA patients before sirukumab treatment from the sirukumab clinical cocktail TP-DI study (10) were simulated with the developed virtual RA patient population and the optimized CYP substrate profiles. Model (8,31).…”